Asymmetric hydrogenation is an important method for generating single enantiomer molecules that include intermediates and fine chemicals with applications in the pharmaceuticals, biotechnology, agrochemical, food, flavours, essential oils, personal care and advanced materials industries. Each enantiomer may have quite different properties and effectiveness. The use of a drug molecule as a single enantiomer reduces the risk of negative effects of a racemate, increases efficacy and accuracy of dosage, reduces the dosage compared to racemates by one half, with a subsequent reduction in cost and waste, environmental burden including agricultural and human waste run-off. This is particularly true since the US Food and Drug Administration, the European Committee for Proprietary Medicinal Products and other regulatory authorities have required characterization of enantiomers in proposed marketable drug products. Examples of some of the top selling drug products that are chiral are: Lipitor™, Zocor™, Zyprexa™, Norvasc™, Procrit™, Prevacid™, Nexium™, Plavix™, Advair™ and Zoloft™. In 2003 the total global sales for these products amounted to 48.3 billion dollars.
In the biotechnology sector the ability to synthesize enantiomerically pure amino acids, peptides and proteins is of great value. In the agrochemical business about 25% of the members of several classes of pesticides and herbicides exist as enantiomers. Currently the largest scale asymmetric hydrogenation process is the production of the S enantiomer of Metalochlor™.
Volatile, enantiomerically pure alcohols are particularly valuable in the flavours and fragrances industries where each enantiomer provides a distinctive olfactory sensation. They are playing an increasingly important role in aromatherapy.
Single enantiomer helical molecules impart important optical, electronic and magnetic properties to materials and nanomaterials with applications in switches, motors, sensors, polarizers and displays.
In the hydrogenation of complex molecules, the selectivity and activity of the process is dependent on the catalyst structure. This structure must interact with the substrate to provide the diastereomeric transition state of lower energy that leads to the required enantiomer.
Conventional asymmetric hydrogenation catalysts utilize platinum group metals (PGM) ruthenium, osmium, rhodium, iridium, palladium or platinum (De Vries et al., “Handbook of Homogeneous Hydrogenation” Wiley-VCH, volumes 1-3, 2007). Their ability to activate hydrogen gas toward addition to organic compounds is well known. However, these metals present potential toxicity problems and prolonged usage of pharmaceuticals containing traces of these metals might lead to harmful bio-accumulation. PGM are expensive and thereby add to the cost of the final product. In addition, they are in limited supply and will decrease in availability over time.
The direct hydrogenation of carbonyl and/or imine groups in an organic molecule using hydrogen gas is now becoming the preferred “green” method because no waste is produced and the separation of product is easier. Hydrogen is expected to be an even more abundant feedstock as it is used more as a green fuel. In a complimentary way, the catalytic hydrogenation or asymmetric hydrogenation of carbonyl and/or imine groups in an organic molecule by transfer from a hydrogen-donating molecule or mixture has the advantage of operational simplicity by avoiding the use of pressurized hydrogen (Gladiali et al., “Asymmetric transfer hydrogenation: chiral ligands and applications,” Chem. Soc. Rev. 35 (2006) pp 226-236).
The reduction of ketones is one of the fundamental reactions in the chemistry field and is used in many chemical transformations towards various products. Asymmetric reduction of the carbonyl group was achieved in the past using chiral catalysts that are based on platinum group metals (PGM) such as ruthenium, rhodium, iridium, palladium or platinum. Usually iPrOH or H2 are used as a reducing agent in those transformations when they are activated by the metal-catalysts. The activation is normally produced via the in situ formation of the catalyst from pre-catalyst by the addition of a strong base.
Reduction catalysis utilizing molecular hydrogen is more attractive compared to the reduction with iPrOH because of the low price of hydrogen gas, product purification simplicity and waste elimination. Reduction catalysis by hydrogen transfer from iPrOH is preferred when pressurized hydrogen gas is not available or convenient.
Chiral alcohols and amines that are produced by the asymmetric hydrogenation or asymmetric transfer hydrogenation of ketones and imines, respectively, are extensively used in the synthesis of pharmaceuticals, agricultural chemicals, fragrances and materials. A non-limiting list of the examples of such compounds is presented below:

Product 1 can be used in preparation of the (+)-compactin, an HMG-CoA-reductase inhibitor. Product 2 can be used in the synthesis of 2,4-diaminoquinazoline derivatives which are possible SMN2 promoter activators which can be used in the treatment of spinal muscular atrophy. Product 3 may be used as a synthetic building block of the highest selling drug Fluoxetine (Prozac®). Product 4 may be used as a chiral synthetic intermediate in preparation of the benzazepine dopamine antagonist Sch 39 166.
Although some PGM catalytic systems have enzyme-like enantioselectivities and activities, their toxicity and high price make them unattractive for some industrial synthetic transformations.
Attempts have been made to solve this problem. For example, Gao et al. in 1996 in the journal Polyhedron (Gao et al. “Synthesis and characterization of iron(2+) and ruthenium(2+) diimino-diphosphine, diamino-diphosphine and diamido-diphosphine complexes,” Polyhedron 1 (1996), pp. 1241-1251) reported the synthesis of iron complexes with tetradentate ligands. The use and application of their iron complexes towards hydrogenation was not disclosed. They reported the synthesis of two iron complexes with diphosphinediimine ligands 6 and 7: trans-[Fe(NCMe)2(6)](ClO4)2 and trans-[Fe(NCMe)2(7)](ClO4)2.

They also reported the iron complex with the diphosphinediamine ligand 8.

Further, Gao et al. in 1996 in the journal Organometallics (Gao et al., “A ruthenium(ii) complex with a c-2-symmetrical diphosphine/diamine tetradentate ligand for asymmetric transfer hydrogenation of aromatic ketones,” Organometallics 15 (1996), pp. 1087-1089) disclosed that ruthenium complexes with the enantiopure ligands 9 ((R,R)-cyP2N2) and 10 are catalysts for the asymmetric transfer hydrogenation of ketones with the latter displaying superior activity and selectivity. Rautenstrauch et al. (Rautenstrauch et al., “Hydrogenation versus Transfer Hydrogenation of Ketones: Two Established Ruthenium Systems Catalyze Both,” Chem. Eur. J. 9 (2003), pp. 4954-4967; U.S. Pat. No. 6,878,852 B2 5/2005 to Rautenstrauch et al.) showed that similar ruthenium complexes are active for the hydrogenation and asymmetric hydrogenation of ketones.

Boaz et al. (U.S. Pat. No. 6,690,115 B2 7/2003 to Boaz et al.; 2006/0135805 A1 to Boaz et al.) made ketone hydrogenation catalysts based on PG metals such as Ru and Rh in complexes of PNNP ligands of the type 11. Here the iron is part of the ferrocenyl substituent on the ligand which is known in the art to provide selectivity and sometimes activity to a PG metal catalyst.

Chen et al. (Chen et al., “Asymmetric transfer hydrogenation of ketones catalyzed by chiral carbonyl iron systems,” Huaxue Xuebao 62 (2004), pp. 1745-1750) reported an asymmetric transfer hydrogenation system where one of the compounds 10, 12 or 13 of the type P—NH—NH—P are added to [HFe3(CO)11]− to generate in situ catalysts for the transfer of hydrogen from isopropanol to ketones but the activity was low and the nature of the active catalyst was thought to be a cluster containing the three irons. The structure of this catalyst remains unknown. Other iron precursors Fe(CO)5 and [Fe(C5H5)(CO2]2 did not lead to active catalyst mixtures.

Bianchini et al. (Bianchini et al., “Chemoselective Hydrogen-Transfer Reduction of alpha,beta-Unsaturated Ketones Catalyzed by Isostructural Iron(II), Ruthenium(II), and Osmium(II) cis Hydride eta(2)-Dihydrogen Complexes,” Organometallics 12 (1993), pp. 3753-3761) reported that iron complexes with a tetradentate PP3 ligand were active for the non-asymmetric hydrogenation of olefins under mild conditions.
Enthaler et al. (Enthaler et al., “Biomimetic transfer hydrogenation of ketones with iron porphyrin catalysts,” Tet. Lett. 47 (2006), pp. 8095-8099) reported that in situ-generated iron complexes of achiral porphyrin ligands are somewhat active for the hydrogenation of ketones but no asymmetric hydrogenation reaction was possible because of the lack of a chiral ligand.
Casey's group (Casey et al., “An efficient and chemoselective iron catalyst for the hydrogenation of ketones,” J. Am. Chem. Soc. 129 (2007), pp. 5816-5817) reported that an achiral complex of the type Fe(arene-OH)H(CO)2 is a hydrogenation catalyst but not an asymmetric hydrogenation catalyst for ketones and imines at room temperature. It also catalyzes the hydrogenation of acetophenone by transfer from isopropanol. The complex [NMe4][Fe3H(CO)11] catalyzes the complete conversion of ketones to alcohols at 80-100° C. within 1-24 h by using alcohols as the reductant (Jothimony et al. “Mechanism for transfer hydrogenation of ketones to alcohols catalyzed by hydridotriiron undecacarbonylate anion under phase transfer conditions,” 52 J. Molec. Cat. (1989), pp. 301-304) but this is not an asymmetric reduction. Bart et al. (Bart et al., “Preparation and molecular and electronic structures of iron(0) dinitrogen and silane complexes and their application to catalytic hydrogenation and hydrosilation,” J. Am. Chem. Soc. 126 (2004), pp. 13794-13795) have reported achiral iron catalysts that hydrogenate olefins under mild conditions.
Thus, there is a need for new catalysts for hydrogenation, asymmetric hydrogenation, transfer hydrogenation, and asymmetric transfer hydrogenation which do not require the use of PGMs.